Methods of preparing stilbene derivatives



Patented Nov. 5, 1946 METHODS OF- PREPARING STILBENE DERIVATIVES Otto Schwarzkopf, New York, N. Y., assignor to Burton T. Bush, Incorporated, Delawanna, N. .L, a corporation of New Jersey No Drawing. Application November 19, 1943, Serial No. 510,976

Claims.

The invention relates to the preparation of stilbene derivatives and particularly hydroxy-stiL.

bene compounds of the general formula:

no-canl-c=c-cflnlon wherein R1 and R2 are identical or different alkyl radicals, preferably of four or less carbon atoms, and the hydroxyl radicals are in any positions on the benzene nuclei, but preferably the para position, and including both the cis and the trans isomers with regard to the positions of the radicals R1 and R2, this patent being a continuationin-part of my application, Serial No. 424,474, filed December 26, 1941.

These substances are important because of their estrogenic activity, particularly the highly active form thereof which is trans-4,4'-dihydroxy, alpha,alpha'-diethylstilbene, and to which this invention more specially relates. They are known substances, described by Dodds (Nature, vol. 141, page 248 (1938) and Proc. Royal Society, vol. 127, page 140 (1939)), but the processes by which they have heretofore been made are expensive to practice and the yields are not high. By this invention these products are more economically obtained by a process which avoids the successive steps of hydrolysis and dehydration necessary in prior proposals, and yields the more desirable trans isomer in predominating ratio.

Referring to the Dodds process, the starting material wa a. ketone of the formula:

, RI and by reaction with a Grignard reagent (RzMgHal) was converted to an oxymagnesium halide compound, of the general formula (I which was hydrolized to a carbinol, of the general formula OH R40C5H4CH-b-CaH4-O R3 and then dehydrated to a dialkoxy-dialkyl-stilbene, viz:

R40C6H4-C(R1) =c Ri CsI-I4OR3 which was dealkylated to form a dihydroxy- 5s ride, and the like, and among the organic acid 2 dialkyl-stilbene within Formula I above, the hydroxy radicals being in the para positions.

The starting material for this invention may be any substance within Formula II. R1, R2, R3,

and R4 in all cases represent the same or different alkyl radicals. Such formula, II, shows that two diastereo-isomeric racemates may exist, but for thi invention itis unimportant which of the two is present or whether both are present.

Solutions, containing one or both of such racemates, have also been used by Braker (U. S. Patent No. 2,252,696) in the same way as Dodds, also by Fieser (U. S. Patent No. 2,248,019).

Said starting substance may be obtained by the Dodds process, or by the action of a Grignard reagent, for example methyl-magnesium-iodide, ethyl-magnesium-bromide, etc., upon the carbinol such as obtained by Dodds (whereby the Grignard reagent reacts with the hydroxy group forming methane, ethane, etc.) or it may be prepared according to said application, Serial No. 424,474, by the action of a Grignard reagent, such as upon a ketonic compound Rs0-CeH4CORz. In all cases the structural forms of the reagents selected to make the starting material are preferably such as have their alkoxy radicals in para positions, thereby producing a starting substance,

Within Formula II, in which such radicals are similarly located and a, final product in which the hydroxy radicals also occupy the para positions, which isdesired.

- Broadly stated the new process comprehends inorganic acid anhydrides are phosphorus pentoxide, sulfur trioxide, etc. On the organic side, among the acid halides, are acetyl chloride, stearyl chloride, benzoyl chloride, propionyl chlo- 3 anhydrides, are propionic anhydride, acetic anhydride, phthalio anhydride, etc.

I am aware that acid halides as well as acid anhydrides have been used in the prior art processes, but they were there used only for dehydrating carbinols and not for'direct conversion (without hydrolysis and subsequent dehydration) of any such oxymagnesium halide compound as is represented by Formula II above.

It can be assumed that the primary result of the reaction of the selected agent on a substance of Formula II is the formation of an ester of the formula wherein Ac is the radical of the acid derivative employed.

These esters are transitory and decompose immediately to yield the stilbene derivative If organic acid halides are used, it is possible under appropriate conditions-such as low reaction temperature, use of equimolecular quantitles of the acid halide and short reaction time, to isolate these esters from the reaction mixture (which in any event will contain some of the compound of Formula IV). They can be subsequently converted, as intermediates, to the stilbene derivative (IV) by different ways, according to the stability of the particular ester. Some of them by simply standing at room temperature will be split and others must be heated to temperatures between ISO-200 C., or be distilled at this temperature, to yield the stilbene derivative.

The isolation of these intermediates and their subsequent conversion to the stilbene is included in this invention although the direct conversion is preferred and is generally sufiiciently accomplished by using moderate temperature and some excess, say of the acid halide or the anhydride, disposing of the excess afterwards by treatment with ethanol, for example.

The alkoxy substance of Formula IV is next dealkylated to yield the product dihydroxy-dialkyl-stilbene of Formula I, and this is preferably done by reacting it with a solution of alkali metal hydroxide in one of the polyhydric alsohols at a temperature between 180 and. 250 C. and at atmospheric pressure, and then liberatin the hydroxy-compound from the alkaline solution by treatment with any acid stronger than the hydroXy-compound, e. g. HCl, H2804, CO2 etc. The polyhydric alcohols suitable for this purpose are those in which the alkali metal hydroxide is soluble either at room or elevated tem perature and which have boiling points above 150 C. and preferably above; 180 0., for ex ample, ethylene glycol, diethylene glycol, propylene glycol, glycerol.v

Such alkaline dealkylation is equally effective whether the alkoxy group occurs in only one or both sides of theformula and it is also possible to obtain dealkylation of only one of the two alkoxy groups, which can be done by simply I terminating the treatment at the appropriate point, as indicated by test of samples.

In further explanation of the invention, the following illustrative examples are given:

To prepare the starting material used in the following examples, 28.4 g. ethyl de'soxyanisoin oH3o-o@Hlco- :H(c2H51) -C6H4-OCH3) dissolved in 50 cc. of ethyl ether was added at a temperature between 0 C. and 35 C. to a Gris nard reagent prepared in known way from 3.5 g. magnesium covered with 70 cc. of ether and 15.6 gr. of ethyl bromide (or corresponding amount of other halide) dissolved in 90 cc. of ether. The solution was allowed to stand over night and then decanted from the unreacted magnesium. The volume was then brought to 220 cc. This is a solution of an oxymagnesium halide compound within Formula II, being "To 220 cc. of a solution prepared as above there was added at room temperature a solution of 11 g. phosphorus oxychloride, POC13, in 25 cc. ether. The mixture remained over night and the ether was then distilled on and after standing for a day at room temperature, 90-100 cc. of ethanol was added while stirring the batch. After cooling, trans-4,4dimethoxy-alpha,alpha-diethylstilbene (21-25 g.) crystallized and was filtered, washed and dried (yield 72%-86%) melting point 122 C. The dealkylation was made by heating this substance with a solution of KOH (41-50 g.) in diethylene glycol (180-220 g.) at 180-215 C. for twenty hours atmospheric pressure. Before heating the air was displaced by nitrogen. After the dealkylation was completed, crude trans-4,4 dihydroxy a1pha,alpha diethylstilbene was precipitated with HCl (150 cc. conc. I-ICl diluted With 150 cc. H2O). The precipitate was filtered, redissolved in a solution of 20 g. KOH in 100 cc. H20 which solution was filtered and the substance was again precipitated with HCl as before. The material was then dissolved in ether, washed with sodium bicarbonate (saturated solution), the other solution was dried, the ether distilled OE and the residue recrystallized from 5 times its weight of ethanisyl-hexane-3-ol, of melting point crystallized from ethylene dichloride (M P. 167-169 0.).

Example 2 To 220 cc. of the solution as above, there were added 19 g. of p-nitro benzoyl chloride at room temperature. The mixture stood for twenty-four hours, andwas then poured into cc. of cold water. The water was extracted with ether, and the ether washed with sodium carbonate and water. The solution was then dried, the ether removed, the residue crystallized from ethanol yielding the ester, p-nitrobenzoate' of 3,4-di- 122 C. which is convertible by heating into dimethoxy diethylstilbene, as above pointed out.

Example 3 To 220 cc. of the solution as above, there wasadded dropwise a solution of 18 g. sulfuryl chloride dissolved in 100 cc. of ;ether. The mixture stood over night at room temperature. Then the ether was distilled off and the residue stood for one day. Then 120 cc. of ethanol were added with stirring until the mass cooled'to room temperature. Trans 4, 4 dimethoxy,alpha,alphadiethylstilbene crystallized and was filtered, and finally dried (yield g. M. P. 122-4 C., 50%) being convertible to trans-4,4 dihydroxy,alpha, alpha-diethylstilbene by dealkylation as before.

' Example-4 To 220 cc. of the solution as above was added at room temperature dropwise a solution of 16 g. acetyl chloride in 50 cc. of ether. The mixture stood for 4 days at the same temperature. Then the ether was distilled off; the residue kept for 1 day. Then 120 cc. of ethanol were added. Trans 4,4 dimethoxy alpha,alpha' diethylstilbene crystallized (yield 21 g., M. P. 122-4 C. 72%) and was dealkylated and worked up as described above.

Example 5 To 220 cc. of the above solution was added dropwise a solution of g. of benzoyl chloride (CeHsCOC'l) in 100 cc. of ether. After standing for 1 hour at room temperature, the ether was distilled ofi. The residue stood over night, then 100 cc. of ethanol were added. Trans-4,4-di methoxy alpha,alpha-diethylstilbene crystallized (yield 21 g., M. P. 122-3 C., 72%) and was dealkylated and worked up as described above.

Example 6 Example 7 To g. of P205 with 300 cc. of xylene, there was added 220 cc. of the above solution. The ether was distilled off and suspension heated to 130 C. under vigorous stirring for 4 hours. Then the xylene was distilled off and the residue stood over night. 100 cc. of ethanol were then added and after cooling trans-4,4-dimethoxy-alpha,

alpha-diethylstilbene crystallized and was filtered and treated as said before (M. P. 122-4 C.)

Example 8 To 220 g. of the solution as above was added a solution of 17 g. of thionyl chloride in 100 cc. of

ether. It stood over night, the ether was distilled ofi and to the residue were added immediately 100 cc. of ethanol. Trans-4,4-dimethoxy,alpha, alpha'-diethylstilbene was obtained (M. P. 122-3 C.)

Example 9 To 220 cc. of the above solution there was added dropwise in 2 hours a solution of 11 g. of acetyl chloride in 100 cc. of ether at room temperature. After 30 min. standing, the mass was poured into 200 cc. of a 5% solution of sodium bicarbonate. The ether layer was separated, washed with water and dried over sodium sulfate. The ether was then distilled off leaving a residue to which was added 100 cc. of ethanol, 4

g. of trans-4,4-dimethoxy alpha,alpha-dieth 'ylstilb'ene crystallized out. After. evaporating the alcohol, the liquid residue contained essentially the acetate of 3,4-dianisyl-hexane-3-ol. This was converted into trans-4,4-dimethoxy-alpha,- alpha'-diethylstilbene by prolonged standing, also by distillation in vacuo, and thereafter demethylated. In a similar way other esters, stearates, for example, can be formed and then converted into'the desired stilbene derivative.

From the above examples it'will be apparent that the members of the group referred to are effective reagents for producing the unsaturated stilbene form from a starting material of the kind mentioned, and that they tend to yield the trans isomer in preference to the other. The reaction is found to be indifferent to the particular positions on'the benzene nuclei of the methoxy (or alkoxy) groups in the starting material, and as might be expected, the original position persists through to the stilbene product. Also, and as the case with other stilbene processes the reaction pattern is the same regardless of the identity of the alkyl groups (R1, R2, R3, and R4) whether the same" or different. Thus, 4,4- dimethoxy-alpha,alpha"-dimethylstilbene M. P. 128 C.) can be produced according to this invention from a solution containing the homolog prepared by the reaction of methyl magnesium iodide and methyl desoxyanisoin, to be then demethylated as above described to the corresponding dihydroxy compound (M. P. 195 0.); and 4,4-dimethoxy alpha methyl,alpha-ethylstilbene (B. P. C./0.1 mm.) can be produced from the homolog prepared from ethyl magnesium iodide and methyl desoxyanisoin, and other alkyl radicals such as propyl-, isopropyl, butyl, isobutyl, etc. can be introduced in the side chain in positions R1, R2 in the stilbene derivative if that should be desired, or in the positions R and R4.

I claim as my invention:

1. The process for preparing the trans-compound having the structural formula:

CHsO

which comprises mixing the compound having the structural formula:

0 M gHalogen OCH;

CzHn

OM a OOH.

which comprises mixing the compound having the structural formula:

OMgBr i C2Hs 02115 with a compound selected from the group consisting of acid halides and acid anhydrides; and

isolating the said trans-compound thus produced. 3. The process for preparing the 'trans-compound having-the structural formula:

which o prises mixin t e eompoundhavin the structural formula:

with acetyl chloride; and isolating the said transcompound thus produced.v

51,, The process for preparing the pound having the structural tormula:

CaHa

trans-com 20 8 which comprises mixing the compound having the structural formula:

OMgBr with phosphorus oxychloride; and isolating the said trans-compound thus produced.

5. The process for preparing the trans-compound having the structural formula:

which comprises mixing the compound having the structural formula:

OCH:

' 0M Br i g lsHa (12H;

with sulfuryl chloride; and isolating the said trans-compound thus produced.

OTTO SCHWARZKQPF. 

